T helper 2 (Th2) cells orchestrate allergic asthma. Inhibition of the Th2 response has been the target of many therapeutic strategies with only marginal success. Our recent studies have demonstrated that the administration of immunostimulatory sequence oligodeoxynucleotides (ISS-ODN, also known as CpGODN) inhibits Th2 responses and suppresses experimental asthma. Interestingly, these effects do not require a simultaneous antigen/allergen administration. The molecular pathways, which drive the ISS-induced inhibition of Th2 cells and the ISS-induced suppression of experimental asthma, have yet to be identified. We reason that the inhibition of the Th2 response by ISS-ODN is secondary to ISS-induced innate cytokines such as IFNs, IL-12 and IL-23 produced by TLR9 bearing APCs. Thus, we will focus our investigation in SA-1 on the signaling events originating at the cytokineR essential for Th2 cell function and survival. We will initially identify the altered cytokineR repertoire on Th2 cells, which makes them responsive to type 1 cytokines (e.g., IFNs) and resistant to type 2 cytokines (e.g., IL-4/IL-13). These studies will be followed by investigations aimed at exploring the changes in the transcriptional program in ISS-induced immunomodulated Th2 cells and the consequent phenotypic change that they undergo. Finally, we will address the ability of immunomodulated Th2 cells to proliferate and to resist pro-apoptotic signals upon allergen challenge. The information obtained in SA-1 will be used in SA-2 to further address the molecular events induced by ISS-ODN administration that lead to the inhibition of experimental asthma. Specifically, we will study the mechanisms by which ISS-ODN convey resistance of lung tissue to pro-asthmatic stimuli triggered by Th2 cells (e.g., IL-13) and the mechanisms by which ISS-ODN inhibits the homing/trafficking of Th2 cells into the airways. Finally, the fate of the ISS immunomodulated Th2 cells in the lung will be assessed. The information obtained in this application will be important to define as it could validate the use of ISS-ODN as a novel class of an immunomoduating agent and would facilitate its therapeutic use in the field of clinical allergy.